Battling the Bulge

Texas Tech researchers fight multi-front war on global obesity epidemic.

Collage of the myriad contributors to the complex problem of obesity.
The problem of obesity is one that stretches far beyond lifestyle and touches every aspect of a person’s life.

Our scientific understanding of obesity has gone past the couch potato concept. In more than a quarter century of studying obesity, Texas Tech professor of nutritional sciences Naima Moustaid-Moussa said it’s not just a matter of laziness. It’s true that sedentary lifestyles, poor eating habits and lack of exercise play a role, but the longer she’s looked at the reasons for skyrocketing obesity, the more variables come into play. It’s a global problem, Naima Moustaid-Moussa said. Even in countries where some might not have enough to eat, obesity has gained a foothold.

Obesity is very complex and due to several reasons, she said. I want to make sure that we convey that. People need to understand obesity is not a problem of food or physical activity. You can have obesity for a variety of reasons.

The problem certainly hasn’t improved in the United States, either. Last year, obesity rates surpassed 35 percent in three states, according to Arkansas, West Virginia and Mississippi all earned the dubious top honors (35.9, 35.7 and 35.5 percent respectively). Texas came in at 11th with 31.9 percent.

Compare that to 1990 when Mississippi came in first with a 15 percent obesity rate, Washington, D.C., stood at 14.4 percent and Pennsylvania, 13.7 percent. The rates have more than doubled in a quarter century.

The state of obesity in the united states as depicted with a "Heat Map" for obesity hotbeds and growing obesity rates.

Doctors and healthcare officials began hearing the rumblings of the oncoming obesity epidemic in the late-’80s, Moustaid-Moussa said. At the time, sedentary lifestyle seemed the easy answer, and many regarded obesity as an American disease.

The rates of obesity were increasing in the ’80s, and mostly in the United States, Moustaid-Moussa said. But that was mainly because more data were available here. Since the 1990s, it’s been going up, and obesity is everywhere, including in third-world countries where it doesn’t make sense. There are people suffering malnutrition and obesity at the same time.

As the epidemic continued, scientists have uncovered a plethora of reasons why obesity rates have ballooned. They have discovered infection from viruses, genetics, food, sleep, brain and body chemistry and psychology also play a role.

The more we know, the more we understand how complex it is, she said. For example, Pima Indian tribes in Arizona have a higher rate of obesity and diabetes than tribes from a similar heritage in Mexico. The driver for this is genetics. People with certain mutations in some genes have increased susceptibility of obesity and other diseases. Some researchers have said that genetics loads the gun and environment pulls the trigger. This describes it very well. It’s not just genes and it’s not just the environment. It’s the complication of the two that makes the difference.

That’s why Moustaid-Moussa created Texas Tech’s Obesity Research Cluster in 2013 to build collaborations between scientists who do obesity research at the university and at Texas Tech University Health Sciences Center (TTUHSC). She, along with Linda Hoover, dean of the College of Human Sciences, and the Office of Research & Innovation, formed the cluster to address the ever-growing problem of obesity.

The cluster provides a platform for people to interact, she said. A few research teams emerged out of this. In a couple of years, we’re going to see some of the seeds we planted and collaborations coming through.

The Accidental Obesitologist

Moustaid-Moussa stumbled upon obesity research in the late 1980s while a graduate student at the University of Paris in France. Originally, she looked at lipid biochemistry and how these fatty molecules can evolve into cholesterol and fatty acids as well as the development and differentiation of fat cells using cell cultures.

Texas Tech professor of nutritional sciences Naima Moustaid-Moussa

In the lab where she worked, one of the top research labs in the country, other scientists were trying to discover why a colony of rats were spontaneously becoming obese.

At that time, in 1989, we were reading about obesity in the United States, she said. Americans were gaining more and more weight. My mentor sent me to a conference in America to present my work on fat cells. He also encouraged me to do the postdoctoral experience. I came to the Keystone Conference on Obesity in Colorado and saw the breadth of research going on in obesity.

Moustaid-Moussa was offered a postdoctoral position at the lab in the Department of Nutrition at Harvard School of Public Health doing cloning of fat cells. While there, she focused on applying new molecular and genetic tools and cloning genes that are involved in fat metabolism to understand how we can control fat cell activity using hormones or nutrients.

Little by little, Moustaid-Moussa said she grew into obesity research. At her first faculty position at the University of Tennessee in Knoxville, she began to develop her own obesity studies program.

By 1993, it was clear that obesity had gained huge attention, she said. I decided to capitalize on the training I had in adipocyte endocrinology and biology. My main question was, ‘If obesity translates into the expansion of adipose (fat) tissue, how does that work?’

Moustaid-Moussa said she knew there was a connection between the expansion of fatty tissues and diabetes and cardiovascular disease.

She focused on developing and using animal models to study fat tissue expansion and regulation in the whole body and used genetic models of obesity as well as diet-induced obesity models using high fat diets.

As experiments commenced, scientists noticed immune cells in adipose tissue and observed how these became a major contributor to obesity-associated inflammation. These immune cells, along with the fat cells themselves and other cell types within adipose tissues secrete inflammatory substances that actually worsen adipose tissue expansion and impair insulin action.

As obesity continues and fat tissue expands, the inflammation worsens, she said. This further increases the risk for diabetes and other metabolic inflammatory diseases that include cancer and heart disease. We found that obesity is a chronic low-grade inflammation. It does, over time, impair the immune system’s abilities. Cancer, fatty liver and diabetes all have inflammation as a common denominator.

Scientists also noticed a strange phenomenon if they gave a mouse eating a high-fat diet, certain fats, such as omega 3 fatty acids. Giving these mice omega 3 actually worked like aspirin and reduced inflammation. Diets enriched with good fats caused the mice to become healthier and lose fat mass.

The fish oil reduced body fat even though the mice were on a high-fat diet, she said. Fewer immune cells got into fat tissue and there was less inflammation.

Currently, Moustaid-Moussa and others are developing a nematode worm to better understand obesity through bioengineering. The worms also accumulate fat in their bodies. Because most of the human genes are also functional in the worm, scientists can generate information that helps them understand human metabolic processes and disease, she said.

The worm will allow these researchers to study fat metabolism and inflammation and other stresses associated with obesity. This is a more cost-effective approach compared to human or rodent studies to generate further hypotheses and findings to be tested in humans and animals.

Moustaid-Moussa, in collaboration with Siva Vanapalli in the Department of Chemical Engineering, Jerzy Blawzdziewicz in Mechanical Engineering, and Shu Wang in Nutritional Sciences, recently received a grant from the U.S. Department of Agriculture to develop the nematode study.

“Dr. Vanapalli’s lab has developed a novel microfluidics device to grow the worms in more controlled conditions than the traditional agar plates and test effects of dietary components such as omega 3 fatty acids in this model as well as mutants strains that develop obesity or have various alterations in fat metabolism,” she said.

Moustaid-Moussa, in collaboration with Siva Vanapalli in the Department of Chemical Engineering, Jerzy Blawzdziewicz in Mechanical Engineering, and Shu Wang in Nutritional Sciences, recently received a grant from the U.S. Department of Agriculture to develop the nematode study.

The worm will allow these researchers to study lipid/fat metabolism and inflammation and oxidative stress associated with obesity. This is a more cost-effective approach compared to human or rodent studies to generate further hypotheses and findings to be tested in humans and animals.

Dr. Vanapalli’s lab has developed a novel microfluidics device to grow the worms in more controlled conditions than the traditional agar plates and test effects of dietary components such as omega 3 fatty acids in this model as well as mutants strains that develop obesity or have various alterations in fat metabolism, she said. Worms also accumulate fat in their bodies.

The Elephantine Explanation

As he sits at a conference table in his office, Dr. Nikhil Dhurandhar, chairman of the Department of Nutritional Science, recalls the tale of six blind men and the elephant. One of the men feels the leg and believes the elephant must be tall and sturdy like a tree. Another touches the animal’s side and thought it must be like a wall. One grabs the trunk and explains the elephant is more a snake.

The Six Blind Men of Indostan accurately described the parts of the elephant they’ve encountered. But in feeling only one part have missed the animal in its entirety. Dhurandhar sees science’s understanding of obesity (or obesities, as he calls them), in terms of this old fable originating from his homeland of India.

Dr. Nikhil Dhurandhar, Texas Tech University Chairman of the Department of Nutritional Science.

We have pieces of the puzzle, but the whole picture still escapes us, he said. Part of that may be remedied by understanding that obesity is obesities in the same way that cancer is not just one type. People are regularly diagnosed with what the American Medical Association classified as a disease only in 2012. However, the one word hardly describes the causes and effects that vary widely with each individual case.

However, unlike cancer, the treatment options are limited and often ineffective. Dhurandhar says doctors can say move more, eat less. They can prescribe from a very short list of available medications. And finally, there’s surgery for a few selected individuals.

An example of gastric ulcer is useful here, he said. In 1910, we understood it to be caused by stomach acid. So treatment approach was ‘no acid, no ulcer’ – and approaches focused on neutralizing the stomach acid. In the ’40s, drugs were developed to address overactive acid-producing cells. In the ’80s, Australian doctors Barry Marshall and Robin Warren discovered a bacteria in people with stomach ulcers, and we finally understood ulcers were mainly caused by infection. We are not there yet with obesity. We are still treating symptoms without completely understanding what’s causing them.

Dhurandhar hopes to find explanations for different types of obesity that lead to varied and more effective treatments depending on the understood circumstances that have led a person to develop obesity.

The son of a pioneering physician who treated obesity in Mumbai for 52 years, Dhurandhar said the health issues of people with obesity were regular dinnertime conversations at his home. His father’s practice encouraged him to start his own in 1983. During the subsequent eight years, he treated about 10,000 patients for obesity. And each time, he advised his patients to eat less and move more.

Many patients lost weight, he said. But I was disappointed I was not able to make a real difference to people’s lives, as they would regain the weight and come right back. That bothered me. I was looking to help more people lose weight more effectively and permanently. I came to the U.S. and got into a graduate program to study nutrition to improve my treatment outcome.

A group of chickens outside.
A chance conversation with a veterinary pathologist led Dhurandhar to look at a virus infection as a possible cause for obesity in humans.

After completing his master’s degree in 11 months, he returned to Bombay in 1988. A chance encounter with veterinary pathologist named S. M. Ajinkya would change his career forever. Ajinkya had recently identified a virus as the cause of an epidemic in the poultry industry in India.

He had just discovered a virus going through the poultry industry in India that was responsible for killing chickens, he said. It was an adenovirus named SMAM-1. So we were just chatting about his discovery. I asked what this virus does to chickens. He said, ‘they get enlarged livers and enlarged kidneys and unusual fat around these organs.’ I said, ‘Wait!’ You just said something. There is fat around the kidneys? Why is there more fat?’ I asked if this could be due to SMAM-1 infection. Most people would have said, ‘you’re crazy to think about a virus causing obesity. Why are you wasting time? No one has ever found that a virus causes obesity.’ Instead, the open-minded researcher that he was, Dr. Ajinkya said, ‘I don’t know.’ Then he said, ‘you are doing a Ph.D. Do some experiments and find out for yourself.

Dhurandhar found in a series of studies that chickens infected with SMAM-1, an adenovirus, not only became fat but also passed the virus along to uninfected cagemates who also became obese.

But he also found another odd piece of data. The SMAM-1 infected obese chickens in the studies also exhibited lower cholesterol and triglycerides, which seemed counterintuitive.

Could a similar virus cause obesity in humans?

After finding antibodies to SMAM-1 adenovirus in some of his obese patients, and with the same odd lower counts of cholesterol and triglycerides, he said he had to find out for sure.

At that point, I decided this is too important to let go, he said. I completed a doctorate in biochemistry, and I decided to close my medical practice and return to the U.S. in the early ’90s.

Dhurandhar got a job in North Dakota and filed over 200 applications and tried for two years to find a lab willing to allow him to pursue his SMAM-1 work. In 1994, he found a home at the medical school at the University of Wisconsin in Madison.

The U.S. Department of Agriculture wouldn’t allow him to import the adenovirus from India. However, he did find a company that sold human adenoviruses – 50 of them. And so, through some intuition and a bit of luck, he made an educated guess on another adenovirus called AD-36. Several successive experiments with various animal models showed that experimental AD-36 infection caused obesity.

Dhurandhar found antibodies to this human adenovirus in American subjects, and those naturally exposed to AD-36 were twice as likely to have obesity.

In the early days, it was extremely difficult to get people to take our research seriously, he said. I suppose, extraordinary claims require extraordinary evidence. Now, I think researchers from every continent except Africa have repeated this research and expanded on it, and I feel vindicated. It feels good to know that we are on right track. I coined the term ‘infectobesity’ to describe obesity of infectious origin.

Dhurandhar hopes to develop a vaccine to prevent AD-36-induced obesity. Also, he and others are raising awareness that there are additional viruses, parasites and microbes that reportedly increase obesity in animal models.

During the ongoing investigation of AD-36, Dhurandhar discovered yet another surprising and counterintuitive effect of the virus – infection effectively improves diabetes in animal models. Dhurandhar and his colleagues discovered the E4orf1 gene of AD-36 as the one responsible for the anti-diabetic effect.

With this gene in hand, they focused on developing an anti-diabetic drug.

We are currently supported by a large grant from a private company to develop this drug and hold several patents needed for such commercialization, he said. Signs are, if we are successful, we will develop a single drug that works for both, type 1 as well as type 2 diabetes. If that happens, this would be a tale about a journey that started with a chance conversation and that ends in a product of significant human benefit.

The Grapes of Allopath

Mankind began cultivating grapes about 8,000 years ago.

The sweet berries not only provided ancient man with a food source, but also led to the innovation of alcoholic drinks, such as wine, thanks to the naturally occurring yeast on the skin of the fruit.

Now, an associate professor of nutritional sciences at Texas Tech is trying to unlock a naturally occurring chemical made by the plant to help fight obesity.

Shu Wang, Ph.D., Texas Tech University Associate Professor of Nutritional Sciences.

Dr. Shu Wang received her medical training from Norman Bethune University of Medical Sciences, her master degree in biochemistry and molecular biology from Capital Medical University, both in China, and her doctoral degree in Nutritional Biochemistry & Metabolism from Tufts University in Massachusetts.

I came to the U.S. in 2000, she said. Chronic diseases account for more than 70 percent of total death in the USA and other developed countries. I really want to use bioactive dietary compounds to prevent or even treat those diseases. I would like to help people, especially people suffering from those diseases. I have started obesity study since 2012, when the ORC was initiated at the Department of Nutritional Sciences at Texas Tech.

Before her appointment at TTU, she also worked in Dr. Paula Grammas’ laboratory at TTUHSC as a postdoctoral research associate.

Obesity is a big public health problem worldwide, she said. For a couple of years, I was thinking about combining nanotechnology and plant phytochemicals to fight obesity. I found out certain compounds extracted from grapes have the potential to treat obesity. The problem is that the way they occur in the plant makes it hard for the body to absorb and deliver to specific tissues.

The state of obesity in the united states as depicted with a "Heat Map" for obesity hotbeds and growing obesity rates.
By manipulating a compound found in grapes, Wang hopes to create a medication that can help fight obesity.

The compound, called resveratrol, doesn’t dissolve in water. The human digestive tract is a watery place, and absorption of the compounds is typically low. The absorbed resveratrol can be metabolized by liver enzymes to become inactive.

Through a grant from the NIH, Wang wants to bring the compounds down to the nano-level, making them more readily absorbed and more stable in the body. She also plans to add compounds to them to help them bond more effectively to cell receptors on certain cells.

The benefit will increase beneficial brown adipose tissue, which in turn will decrease the bodyfat mass by burning it away, she said.

Wang and her team will develop an adipose-targeting nanocarreir system, which can deliver resveratrol to adipose tissues to enhance the anti-obesity efficacy.

The nanocarriers are biocompatible and biodegradable. This innovation could serve as a potential breakthrough in the prevention and treatment of obesity by targeted delivery of natural compounds to adipose tissues with minimized side-effects to other tissues.

Since obesity is a major risk factor for many chronic diseases in the United States, the outcome of this project is expected to improve the quality of life and produce dramatic savings in the cost of medical care, she said. Hopefully we can increase this compound’s ability to dissolve in water and target capacity to increase treatment effectiveness. You don’t need a high dose, but you do want it to go to the right places in the body. At the nanoscale, these compounds can easily cross blood vessels and get into target tissue without floating around in the blood vessels until they are filtered out and eliminated.


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Sharing the Health

Through collaboration, Texas Tech researchers attack obesity together with Obesity Research Cluster.

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